ライフサイエンスコーパス: VUS

1 VUS were introduced into the endogenous Msh2 gene of mou

2 VUSs with evidence in favor of causality were those that

3 everal lines of evidence for LOF of 9 Kir2.1 VUS in the process.

4 /LP variants exhibiting LOF, and 7 out of 10 VUS were LOF, in contrast to the DMS method.

5 The assay identified 12 VUS that did alter function of the gene product and 28 V

6 A total of 133 VUSs had odds of at least 100 : 1 in favor of neutrality

7 Assessment of 136 VUSs interrogating a range of PALB2 biological functions

8 The primary driver of 175 VUS classifications was insufficient evidence supporting

9 r volume, 50%) managed patients with BRCA1/2 VUS the same as patients with BRCA1/2 pathogenic mutatio

10 e enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign.

11 By classifying functional effects for 251 VUS from gnomAD, we reduced the incidence of genotypes o

12 id alter function of the gene product and 28 VUS that did not; the remaining 8 VUS had intermediate e

13 Our results suggest that more than 1 in 3 VUS in ARSA may be pathogenic.

14 be variants of uncertain significance(2-4) (VUS).

15 and 21 in MSH2) and a prospective set of 48 VUS (25 in MLH1 and 23 in MSH2).

16 mi high-throughput functional analysis of 48 VUS in human PALB2.

17 /54 [22%] likely pathogenic, and 30/54 [56%] VUS; P=not significant).

18 Nineteen of the 59 VUS were identified as pathogenic.

19 uct and 28 VUS that did not; the remaining 8 VUS had intermediate effects on MMR capacity and could n

20 Eleven of the 87 VUS were tested, and 4/11 were found to have an impact o

21 ed variant set included 28 P/LP variants, 96 VUS, and 34 LB/B variants, mostly in cancer (40%) and ca

22 ) as likely pathogenic, and 49/70 (70%) as a VUS.

23 dditional 21% of patients with ALS carried a VUS in an ALS-associated gene.

24 An additional N=25 had a VUS reclassified as a "VUS-of-interest" affecting a posi

25 revealed all to be deleterious, including a VUS.

26 the assessment: co-occurrence in trans of a VUS with known deleterious mutations; detailed analysis,

27 ed disease causality for BRCA1 p.V1688del, a VUS recurrent in Italian breast/ovarian cancer families.

28 additional N=25 had a VUS reclassified as a "VUS-of-interest" affecting a positive outcome measure.

29 onfident than cardiologists counseling about VUS results (P<0.001); while both cardiovascular GCs and

30 nine allowed the detection of MMR-abrogating VUS.

31 When applied to 33 additional VUS, the classifier identified eight with 99% or more pr

32 Prediction scores were calculated for all VUS according to the recommendations of the American Col

33 ovide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be u

34 of test results were BRCA1/2, PVs 11.0%, and VUS 0.9%; breast or ovarian genes, PVs 4.0%, and VUS 12.

35 0.9%; breast or ovarian genes, PVs 4.0%, and VUS 12.6%; other actionable genes, PVs 0.7%, and VUS 0.4

36 er cases in 2017 were BRCA1/2, PVs 5.2%, and VUS 0.8%; breast cancer-associated genes or ovarian canc

37 and VUS 0.4%; and other genes, PVs 0.3%, and VUS 0.6%.

38 and VUS 0.5%; and other genes, PVs 0.3%, and VUS 2.6%.

39 D, SMAD4, TSC1, TSC2, and VHL) PVs 0.6%, and VUS 0.5%; and other genes, PVs 0.3%, and VUS 2.6%.

40 12.6%; other actionable genes, PVs 0.7%, and VUS 0.4%; and other genes, PVs 0.3%, and VUS 0.6%.

41 51C, RAD51D, STK11, and TP53), PVs 3.7%, and VUS 12.0%; other actionable genes (APC, BMPR1A, MEN1, MU

42 measures in patients with P/LP variants and VUS showed no significant differences, and regression an

43 e present in two subjects (4%; p = 0.21) and VUSs in 12 subjects (25%; p = 0.64).

44 IRT can be applied to any VUS of interest and each candidate nearby gene to output

45 ); 56% of variants within CVD risk genes are VUS, and machine learning algorithms trained upon large

46 e classified as P/LP, 16 as B/LB, and 193 as VUS.

47 Over half of these variants are annotated as VUS by clinical diagnostic laboratories.

48 lines classified 47% of all RYR2 variants as VUS.

49 e testing laboratory, 154 were classified as VUSs without functional data.

50 ssential splice sites and were classified as VUSs.

51 ariants that had been previously reported as VUSs, offering the potential to identify additional peop

52 ted RYR2 VUS and long QT syndrome-associated VUS in KCNQ1, KCNH2, and SCN5A by developing gene-specif

53 ow 2 deep protein language models perform at VUS resolution in the 3 most common long-QT syndrome-cau

54 es for characterizing large numbers of BRCA1 VUSs.

55 Among all BRCA2 VUS, those causing partial/leaky splicing defects are th

56 he importance of correctly classifying BRCA2 VUS as pathogenic variants can impact both future cancer

57 functional assay to characterize eight BRCA2 VUS that affect highly conserved amino acid residues and

58 n to determine the cancer relevance of BRCA2 VUS.

59 In this study, we identified three BRCA2 VUS located within the BRC repeat region to determine th

60 nt an adjunct to sequencing for categorizing VUS or may represent a stand-alone measure for assessing

61 , including highly suspected disease-causing VUS, and turnaround time for rapid results.

62 Functional characterization of CDKN2A VUSs is needed to reclassify variants and inform clinica

63 Therefore, CDKN2A VUSs may play a significant, unappreciated role in risk

64 l data is one evidence type used to classify VUS.

65 Finally, a damaging VUS in CHEK2, c.486A>G/p.D162G, was also identified, whi

66 hus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk.

67 lines alone failed to significantly decrease VUS burden in 2 independent cohorts.

68 he capability of algorithms to differentiate VUSs away from the immediate splice site as being 'patho

69 med the ability of the assay to discriminate VUS that affected the function of the gene products from

70 ed to provide an overall assessment for each VUS.

71 e to achieve the goal of largely eliminating VUSs by 2030, is largely a consequence of the choices ma

72 two VUS and a benign classification for five VUS.

73 Compared to WT CC2D1A, five VUSs (p.Pro319Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile

74 isease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidat

75 uding medical management recommendations for VUS patients and their families, is important to prevent

76 dence of moderate or supporting strength for VUS reclassification.

77 y (64 752 events [61.65%]) were changes from VUS to either likely benign, benign, likely pathogenic,

78 ariants should be assayed to shift more from VUS to benign or pathogenic classifications.

79 ividuals who had a variant reclassified from VUS to pathogenic/likely pathogenic (P/LP) and 27 indivi

80 valuation and reclassification of several GT VUSs, including alphaIIb Gly201Ala, a population variant

81 %) were deemed to have P/LP variants, 65 had VUS (16.8%) and three benign variants (0.8%; excluded fr

82 ant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potential clinical r

83 igh probability that the corresponding human VUS is pathogenic.

84 e assignment of pathogenicity to these human VUS and validates the approach described here as a diagn

85 essed using prior studies in >900 identified VUS.

86 The majority of identified VUS occur only in one to two individuals; these variants

87 l assays efficiently and reliably identified VUS in CHEK2 that associate with cancer.

88 Deep protein language models aid in VUS resolution with high sensitivity but lower specifici

89 of personal and family history of cancer in VUS-carrying probands; and, in a subset of probands, an

90 ease in positive rate (3.1%) and decrease in VUS rate (-3.9%) was higher in Asian, Black, and Hispani

91 re increase in diagnostic yield, decrease in VUS rate, the overall results by variant type, the assoc

92 A similar drop in VUS rate (14/33 [42%] versus 3/33 [9%]; P=0.001) was obs

93 more genes widened a racial or ethnic gap in VUS results.

94 However, a significant reduction in VUS burden was observed after the addition of phenotypic

95 y uninformative germline findings, including VUS.

96 ing and an effective result return including VUS interpretation.

97 ool to address the challenge of interpreting VUS within genotype-phenotype relationships and NBS.

98 e enabled us to reclassify 6 out of 44 KCNH2 VUSs as likely pathogenic.

99 inical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and t

100 l analyses of one variant, a synonymous LMNA VUS, demonstrated segregation with cardiomyopathy affect

101 In contrast, 41% ClinVar and 61% LOVD VUSs were reclassified into clinically meaningful classe

102 reached complete five-category (i.e., P, LP, VUS, LB, B) concordance, and 17 (11%) had a discordance

103 Consequently, many VUS remain unclassified both functionally and clinically

104 p1, in Chek2 knockout mES cells, 31 missense VUS in CHEK2 were found to impair protein function to a

105 termine the functional impact of 50 missense VUS in human CHEK2.

106 uals found to harbor germline BRCA2 missense VUS.

107 truncating variants, while 9 CHEK2 missense VUS resulted in intermediate functional defects.

108 Analysis of eight missense VUS generated evidence that three are benign (Cys173Arg,

109 gans) for in vivo interpretation of missense VUS alleles of TMEM67, a cilia gene associated with cili

110 tional data and other evidence, ten missense VUS are reclassified as pathogenic/likely pathogenic, an

111 d genes (i) by the number of unique missense VUS that had been reported to ClinVar; (ii) by movabilit

112 idence to resolve the ~1,300 extant missense VUSs in MSH2 and may facilitate the prospective classifi

113 A total of 479 individuals had 1 or more VUS (38%; 95% CI, 35%-41%).

114 ies from benign variants and categorize most VUS as benign.

115 Mechanistically, most VUS impaired CHK2 kinase function by causing protein ins

116 prediction, arguing that many, if not most, VUS in coding regions will be resolved by 2030.

117 ed genes; testing other genes yielded mostly VUS.

118 to give extra weight to reappearing, movable VUS and (iii) by difficulty-adjusted impact scores, to a

119 orphisms and was used to investigate 59 Msh2 VUS.

120 HWA is able to classify MLH1, MSH2, and MSH6 VUSs as either benign or pathogenic with high accuracy.

121 LP] or pathogenic [P]) versus nonactionable (VUS, likely benign, or benign) calls were 95% concordant

122 A total of 72 rare nonsynonymous VUS (9 KCNQ1, 19 KCNH2, and 50 SCN5A) were engineered by

123 verall, 28 of the 33 pilot variants were not VUS, leading to an 85% classification rate.

124 lapping clinical features, each with a novel VUS in the middle domain of DNM1L (p.G350R and p.E379K).

125 with the p.E379K variant also has a de novo VUS in pyruvate dehydrogenase 1 (PDHA1) affecting the sa

126 tegies for screening and characterization of VUS.

127 Classification of VUS as neutral will have immediate benefit for those ind

128 an important role, careful consideration of VUS reveals it to be a nebulous description of genomic i

129 However, Type 3 variants consist of VUS that are less dysfunctional than Types 1 and 2 but a

130 Final models were applied to datasets of VUS identified from ClinVar and exome sequencing.

131 The designation of VUS is a barrier to the use of sequence data in clinical

132 ce burden that would ensue is a detection of VUS of 34%.

133 l line to determine the functional effect of VUS.

134 e adapted this method to test the effects of VUS in MLH1 and MSH2 genes found in patients with suspec

135 thylating agent can determine the effects of VUS in MMR genes and identify patients with constitution

136 eria to reclassify a substantial fraction of VUS.

137 Approximately one-half of VUS reclassifications (37 074 of 64 840 events [57.18%])

138 Interpreting the functional impacts of VUS is challenging but profoundly important for clinical

139 possible in determining the pathogenicity of VUS in CVDs.

140 used to help assessing the pathogenicity of VUS in MLH1 and MSH2 found in patients with suspected Ly

141 method that can predict the pathogenicity of VUS that does not require familial information or segreg

142 ilial data to determine the pathogenicity of VUS.

143 r improving VC methods, reducing the rate of VUS, and generating more definitive results for patients

144 thod for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogen

145 bined with clinical data, eliminating 49% of VUSs for BRCA1, 69% for TP53, and 15% for PTEN.

146 a similar HWA to allow for classification of VUSs in genes associated with Lynch syndrome using data

147 mented a HWA to aid in the classification of VUSs in genes associated with Lynch syndrome.

148 rs' confidence in counseling, explanation of VUSs, topics covered before and after genetic testing, a

149 nt discovery, and clinical interpretation of VUSs.

150 cificity may influence the interpretation of VUSs.

151 rity as (likely) benign. The total number of VUSs was reduced by 37%.

152 It also allowed for the prioritization of VUSs that will benefit from in-depth evidence collection

153 s potential to scale the reclassification of VUSs.

154 hermore, 95% of individuals had at least one VUS.

155 Diagnostic and/or VUS were returned for 51 patients (45%), while 62 (55%)

156 Sample size determination based on AUC or VUS would not only guarantee an overall correct classifi

157 more than one genetic variant (pathogenic or VUS).

158 nign (n = 2), likely pathogenic (n = 10), or VUSs (n = 61).

159 ference between the two approximate AUCs (or VUSs) is below a pre-specified threshold.

160 then used to evaluate the associated AUCs or VUSs, whose accuracies are validated using Monte Carlo s

161 The overall VUS rate was 46.1% for the entire patient population.

162 By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in P

163 facilitate the identification of pathogenic VUS, we have developed an in cellulo genetic screen-base

164 "Pathogenic" VUSs also exhibit mutual exclusivity with known oncogeni

165 istributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam d

166 all previous tools, removing 41% of patient VUS at 95% sensitivity.

167 ed highly ranked CVD pathogenicity predictor VUS meeting clinical pathogenicity criteria, 27.6% had c

168 s, we used computational tools to prioritize VUS and developed a cell-based minigene splicing assay t

169 s approach, we identified that 12.4% of rare VUSs in LDLR seen in participants meet diagnostic criter

170 7 (65%) promising APC variants that remained VUS despite evidence for pathogenicity, a data-mining-dr

171 Overall, we present a rapid assay to resolve VUS in SZT2, identify a founder variant in individuals o

172 ontribution of various strategies to resolve VUS, including emerging machine learning-based computati

173 us 3/42 [7%]; P<0.001) with 13/20 (65%) RYR2 VUS promoted to likely pathogenic and 4/20 (20%) demoted

174 nter validation cohort with 10/14 (71%) RYR2 VUS promoted to likely pathogenic and 1/14 (7%) demoted

175 phic ventricular tachycardia-associated RYR2 VUS and long QT syndrome-associated VUS in KCNQ1, KCNH2,

176 ion approach could reduce the burden of RYR2 VUS encountered during clinical genetic testing.

177 was a greater burden of higher CVD-PP scored VUS in individuals with dilated cardiomyopathy compared

178 the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stabi

179 s variants of unknown clinical significance (VUS) due to the availability of very limited information

180 d variants of unknown clinical significance (VUS) in the related genes.

181 variants of uncertain clinical significance (VUS).

182 variants of uncertain clinical significance (VUS).

183 variants of uncertain clinical significance (VUS).

184 fied as a variant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potent

185 by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance.

186 umber of variants of uncertain significance (VUS) are being identified, the unclassified biological e

187 a higher Variant of Uncertain Significance (VUS) burden.

188 one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretat

189 ified as variants of uncertain significance (VUS) due to lack of epidemiological and functional data.

190 (Kir2.1) variants of uncertain significance (VUS) have been associated with Andersen-Tawil Syndrome (

191 missense variants of uncertain significance (VUS) have been identified, but the effects of the majori

192 ions and variants of uncertain significance (VUS) in 180 medically relevant genes, including all ACMG

193 ractice, variants of uncertain significance (VUS) in genes associated with catecholaminergic polymorp

194 ied many variants of uncertain significance (VUS) in genes associated with inherited arrhythmias and

195 list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in

196 city of a variant of uncertain significance (VUS) is challenging due to the lack of suitable model sy

197 missense variants of uncertain significance (VUS) is in its infancy.

198 ny BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to lim

199 (LP), or variant of uncertain significance (VUS) were not considered as providing evidence for patho

200 10%) and variants of uncertain significance (VUS) were observed in additional 43 SCD victims (28%).

201 or a rare variant of uncertain significance (VUS) with at least moderate evidence of pathogenicity-an

202 agnostic variants of uncertain significance (VUS) with clinical features consistent with the involved

203 ified as Variants of Uncertain Significance (VUS) with unknown functional consequences.

204 ignation 'variant of uncertain significance (VUS)' obsolete." We discuss the prospects for this predi

205 fied as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign.

206 y yields variants of uncertain significance (VUS), creating clinical ambiguity.

207 urden of variants of uncertain significance (VUS), especially missense changes.

208 of these variants of uncertain significance (VUS), focusing on mutator S homolog 2 (MSH2).

209 ants and variants of uncertain significance (VUS), for their effects on DNA binding activity.

210 ore SZT2 variants of uncertain significance (VUS), highlighting the need for functional characterizat

211 y benign, variant of uncertain significance (VUS), likely pathogenic, or pathogenic.

212 2 carry a variant of uncertain significance (VUS), making clinical management less certain.

213 ding the variants of uncertain significance (VUS), potentially significant findings were reported in

214 ions, or variants of uncertain significance (VUS), purifying variant proteins for biochemical and fun

215 of AGXT variants of uncertain significance (VUS), we implemented a platform based on a cellular mode

216 sociated variants of uncertain significance (VUS), which cannot be actioned clinically.

217 dditional variant of uncertain significance (VUS).

218 be reclassified from uncertain significance (VUS).

219 urden of variants of uncertain significance (VUS).

220 enic and variants of uncertain significance (VUS).

221 ents are variants of uncertain significance (VUS).

222 ified as variants of uncertain significance (VUS).

223 tated as variants of uncertain significance (VUS).

224 ously as variants of uncertain significance (VUS).

225 s and 87 variants of uncertain significance (VUS).

226 rols and variants of uncertain significance (VUS).

227 genetic variants of uncertain significance (VUS; higher risk, 43%; average risk, 51%).

228 syndrome, variants of unclear significance (VUS), rather than an obviously pathogenic mutations, are

229 h over 285 variants of unknown significance (VUS) found in primary ovarian tumors.

230 r 500 rare variants of unknown significance (VUS) in the splicing region.

231 ng genetic variants of unknown significance (VUS) is essential in clinical applications of genome seq

232 ay uncover variants of unknown significance (VUS) that require functional validation.

233 Five variants of unknown significance (VUS) were assayed for possible reclassification.

234 suspected variants of unknown significance (VUS) were reported.

235 ication of variants of unknown significance (VUS).

236 these are variants of unknown significance (VUS).

237 ssified as variants of unknown significance (VUS).

238 f variants of unknown clinical significance (VUSs).

239 CDKN2A variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC a

240 and 348 variants of uncertain significance (VUSs) classified as high confidence from ClinVar.

241 ation of variants of uncertain significance (VUSs) in BRCA1 and BRCA2.

242 germline variants of uncertain significance (VUSs) in the BRCA2 cancer predisposition gene remains a

243 missense variants of uncertain significance (VUSs) is a major challenge.

244 ation of variants of uncertain significance (VUSs) remains a challenge in the care of patients with i

245 esolving variants of uncertain significance (VUSs), particularly those affecting gene expression and

246 ified as variants of uncertain significance (VUSs), we propose a refined classificatory framework tha

247 nts with Variants of Uncertain Significance (VUSs).

248 ty or as variants of uncertain significance (VUSs).

249 de human variants of uncertain significance (VUSs).

250 ified as variants of uncertain significance (VUSs).

251 (LP), or variants of uncertain significance (VUSs).

252 missense variants of uncertain significance (VUSs).

253 hich are variants of uncertain significance (VUSs).

254 igned as variants of uncertain significance (VUSs).

255 ified as variants of uncertain significance (VUSs).

256 lence of variants of uncertain significance (VUSs).

257 date are variants of uncertain significance (VUSs).

258 3 sequence variants of unknown significance (VUSs) in the BRCA genes.

259 lp resolve variants of unknown significance (VUSs).

260 deemed "variants of uncertain significance" (VUS).

261 nation, "variant of uncertain significance" (VUS).

262 ted as "variants of uncertain significance" (VUSs).

263 ied as 'variants of uncertain significance' (VUS).

264 ogenicity (variants of unknown significance, VUS).

265 all individuals tested, 5.4% had a splicing VUS.

266 sification, and 312 of 439 existing splicing VUS (71.1%) were resolved by RNA evidence.

267 In ClinVar, splicing VUSs were 4.8% of reported variants and could benefit fr

268 y of RNA analysis for reclassifying splicing VUSs, and how natural variation may confound clinical in

269 t interpretation, we estimated that splicing VUSs would be reclassified in 1.7% of individuals in our

270 ic/likely pathogenic, and only 12 were still VUSs.

271 ained upon large data resources can stratify VUS into higher versus lower probability of contributing

272 Such VUS findings can frustrate the goals of genetic testing,

273 The uncertainty of whether such VUS inactivate MMR, and therefore are pathogenic, preclu

274 and the Volume Under the ROC hyper-Surface (VUS) for three or more classes.

275 In all, 22 out of 32 tested VUSs were reclassified.

276 d reclassification of the majority of tested VUSs in SCN5A.

277 ge of Medical Genetics standards dropped the VUS rate significantly (20/42 [48%] versus 3/42 [7%]; P<

278 ing the combined PE-MYH7-ACMG framework, the VUS decreased significantly from 49 to 27 (P<0.001, Mayo

279 esulted in a nonsignificant reduction of the VUS burden in both cohorts from 49/70 to 39/70 (56%; P=0

280 owed us to tentatively reclassify all of the VUS in our cohort of 12 individuals, identifying five in

281 rotein functional data, 86% (132/154) of the VUSs were reclassified as either likely pathogenic/patho

282 the pathogenic variants and 75 (22%) of the VUSs.

283 o was computed under the hypothesis that the VUSs were equivalent to an "average" deleterious mutatio

284 , our paradigm can also be adapted for their VUSs.

285 zation to determine, which, if any, of these VUS were pathogenic.

286 Three VUS in the coiled-coil domain of PALB2 abrogate the inte

287 ver the information that only contributed to VUS reclassification.

288 ase over the information that contributed to VUS reclassification.

289 ase over the information that contributed to VUS reclassification.

290 ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management.

291 is study is to describe practices related to VUS results including information and medical management

292 ence for a pathogenic classification for two VUS and a benign classification for five VUS.

293 Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21.

294 ryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function.

295 affect clinical recommendations (P/LP versus VUS/LB/B).

296 nic/likely pathogenic (P/LP) variants versus VUS.

297 P and LP, respectively, were discordant with VUS.

298 y half of these critical residues match with VUS previously identified in individuals suspected of Ly

299 Half of average-risk patients with VUS undergo BLM, suggesting a limited understanding of r

300 In two probands with VUSs, pathogenic splicing abnormalities were undetectabl